Dexmedetomidine does not compromise neuronal viability, synaptic connectivity, learning and memory in a rodent model

Abstract

Recent animal studies have drawn concerns regarding most commonly used anesthetics and their long-term cytotoxic effects, specifically on the nervous tissue. It is therefore imperative that the search continues for agents that are non-toxic at both the cellular and behavioural level. One such agent appears to be dexmedetomidine (DEX) which has not only been found to be less neurotoxic but has also been shown to protect neurons from cytotoxicity induced by other anesthetic agents. However, DEX’s effects on the growth and synaptic connectivity at the individual neuronal level, and the underlying mechanisms have not yet been fully resolved. Here, we tested DEX for its impact on neuronal growth, synapse formation (in vitro) and learning and memory in a rodent model. Rat cortical neurons were exposed to a range of clinically relevant DEX concentrations (0.05–10 µM) and cellular viability, neurite outgrowth, synaptic assembly and mitochondrial morphology were assessed. We discovered that DEX did not affect neuronal viability when used below 10 µM, whereas significant cell death was noted at higher concentrations. Interestingly, in the presence of DEX, neurons exhibited more neurite branching, albeit with no differences in corresponding synaptic puncta formation. When rat pups were injected subcutaneously with DEX 25 µg/kg on postnatal day 7 and again on postnatal day 8, we discovered that this agent did not affect hippocampal-dependent memory in freely behaving animals. Our data demonstrates, for the first time, the non-neurotoxic nature of DEX both in vitro and in vivo in an animal model providing support for its utility as a safer anesthetic agent. Moreover, this study provides the first direct evidence that although DEX is growth permissive, causes mitochondrial fusion and reduces oxygen reactive species production, it does not affect the total number of synaptic connections between the cortical neurons in vitro.

Sevoflurane Exposure in Neonates Perturbs the Expression Patterns of Specific Genes That May Underly the Observed Learning and Memory Deficits

“…To assess whether a clinically relevant concentration of sevoflurane had any long-term effects on spatial learning, we used Morris water maze (MWM) as previously described [27,55]. Latency (time required to reach the hidden platform), distance swum, and the trajectory followed by the animals while swimming was monitored during each trial.…”

“…Dexmedetomidine has gained some notoriety in the past years as a possible neuroprotectant agent. Studies have looked at putative mechanisms underlying its neuroprotective effects at the molecular level and shown that dexmedetomidine may downregulate proteins implicated in apoptosis [13,25,51,89], promote neuronal outgrowth [12,55], modify mitochondrial morphology and function [52,55] and decrease inflammatory cytokines [53]. Behavioural studies where DEX was used as a pre-treatment prior to sevoflurane exposure have found improvements in swimming latency [24,90] and object recognition [23,27].…”

“…Animals were placed in a 1.8 m diameter pool of water with a hidden platform at 1 cm below the water surface (25 • C) placed in a room with visual cues on four different walls as previously described [55]. For this study, latency and distances swum were measured with the automated software ANY-Maze (Stoelting Co, Wood Dale, IL, USA) from day 1 to day 5, and the assay was again repeated at days 14, 28, and 56 to assess retention memory.…”

“…Object selection was carried out as previously described [55] using a habituation period of 2 consecutive days where the animal was placed in an empty box for 15 min. After the habituation, the animals went through (1) a familiarization phase where two identical objects were introduced for 5 min, (2) a retention interval where the animals were removed from the box for 5 min, and, (3) a testing phase where the animals were left to interact with a novel object or a familiar object placed at a different location in the box for 5 min.…”

“…Different animal studies have focused on DEX use as a coadjuvant along with other commonly used anesthetics to assess its possible neuroprotective effects. These studies have shown that DEX-mediated neuroprotective effects may involve suppression of apoptotic pathways [13,51,52], inflammation [53,54], or neurogenesis [12,55]. However, an extensive analysis at the level of gene expression has not been performed to better understand how DEX may override the neurotoxic effects of sevoflurane.…”